GENPATH Cancer (4) Cancer Biology Flashcards
Anoikis is […]
Anoikis is a form of programmed cell death where cells detach from surrounding ECM (and neighboring cells)
dMMR and MSI-H phenotype define a **unique biological subset of cancers **that are characterized by:
- […]
- […]
dMMR and MSI-H phenotype define a unique biological subset of cancers that are characterized by:
- **High tumour mutational load
-* Increased responsiveness to anti PD-1 based immunotherapy***
Lead to the approval of anti-PD-1 drug pembrolizumab which covers both MSI-H and dMMR cancer subsets REGARDLESS of specific tumour type.
FYI traditionally, only cancer specific drugs were approved.
Examples of targets oncogenes formation buffet (vvvvvv IMPT!!!)
Growth Factor
- Increased levels of […] in Glioblastoma
Growth factor receptor (esp Receptor Tyrosine Kinase receptors)
- overexpressed […] in 80% of colorectal carcinoma
- Increased […] in a third of breast cancers
- Constitutively active […] in 60% of lung adenocarcinoma
- Constitutively active […] in 5% of lung adenocarcinoma
- Constitutively active […] and […] in gastrointestinal stromal tumour (GIST)
Signal Transduction Protein
- […] mutations (immediately downstream of RTKs) in 90% of pancreatic adenocarcinoma and cholangioocarcinoma, 50% of colon and endometrial and thyroid cancers, 30% of lung adenocarcionoma and myeloid leukemias
- […] mutation in 100% of hairy cell leukemia, 60% of melanoma and 30% of papillary thyroid carcinoma
- […] mutation in 30% of breast cancer
Transcription Factors
- […] mutation in many cancers including Burkitt Lymphoma
Cell Cycle Regulators
- […] (these 2 forms complexes) mutation in many tumors including mantle cell lymphoma, multiple myeloma, breast and esophageal cancers, glioblastomas, melanoma, sarcoma
Examples of targets oncogenes formation buffet** (vvvvvv IMPT!!!)**
Growth Factor
- Increased levels of platelet-derived growth factor (PDGF) in Glioblastoma
Growth factor receptor (esp Receptor Tyrosine Kinase receptors)
- overexpressed EGFR (ERBB1) in 80% of colorectal carcinoma
- Increased HER2 (ERBB2) in a third of breast cancers
- Constitutively active EGFR **in 60% of lung adenocarcinoma
- Constitutively active EML4-ALK fusion protein **in 5% of **lung adenocarcinoma
- Constitutively active* KIT** and **PDGFR ***in gastrointestinal stromal tumour (GIST)
Signal Transduction Protein
- **RAS **mutations (immediately downstream of RTKs) in 90% of pancreatic adenocarcinoma and cholangioocarcinoma, 50% of colon and endometrial and thyroid cancers, 30% of lung adenocarcionoma and myeloid leukemias
- BRAF mutation in 100% of hairy cell leukemia, 60% of melanoma and 30% of papillary thyroid carcinoma
- **PI3K family (PI3K, AKT, mTOR) **mutation in 30% of breast cancer
Transcription Factors
- MYC mutation in many cancers including Burkitt Lymphoma
Cell Cycle Regulators
- cyclins and cyclin-dependent kinases (these 2 forms complexes) mutation in many tumors including mantle cell lymphoma, multiple myeloma, breast and esophageal cancers, glioblastomas, melanoma, sarcoma
You wont be able to understand these cancers now but wh
Mainly for MCQs
Familial adenomatous polyposis coli (FAP) refers the germline loss-of-function mutation involving the […] gene. Affected individuals developes hundreds of adenomatous polyps by 15-20 years old and colon cancer by age 50 (almost inevitable).
adenoma happens when […] are lost
in contrast to sporadic cancer (need 2 mutations), this condition […]
**Familial adenomatous polyposis coli (FAP) **refers the germline loss-of-function mutation involving the APC gene. Affected individuals developes hundreds of adenomatous polyps by 15-20 years old and colon cancer by age 50 (almost inevitable).
adenoma happens when both copies of APC genes are lost
in contrast to sporadic cancer (need 2 mutations), this condition only needs 1 more mutation to APC gene allele
Mechanism wise, basically APC is involved in WNT signalling pathway. In
gene example of inhibitors of cell cycle progression:
-[…]
gene example of enablers of genomic stability:
-[…]
gene example of Inhibitors of mitogenic signalling pathways:
-[…]
-[…]
gene example of DNA repair factors:
[…]
gene example of inhibitors of cell cycle progression:
-Retinoblastoma (RB)
gene example of enablers of genomic stability:
-TP53
gene example of Inhibitors of mitogenic signalling pathways:
-APC
-PTEN
gene example of DNA repair factors:
-MMRs
Germline mutation of one of the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2 gives rise to […] syndrome)(this instability is also referred to as […])
(note that it can also give rise to many many other diseases because mutation is germline)
Germline mutation of one of the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2 gives rise to HNPCC syndrome)(this instability is also referred to as **microsatellite instability (MSI)) **
(note that it can also give rise to many many other diseases because mutation is germline)
HNPCC syndrome is the most common form of hereditary colorectal cancer. Leads to familial colon carcinomas predominantly affecting the caecum and proximal colon.
- Familial Adenomatous Polyposis (FAP) is characterized by lots of polyps
- Hereditary nonpolyposis cancer syndrome (HNPCC) is characterized by colorectal carcinoma that affects right side of colon
Hallmark 10: Tumor-Promoting Inflammation
Tumour associated inflammatory response has the unanticipated, paradoxical effect of enhancing tumourigenesis and progression.
Inflammation (largely […] immune system) can contribute to multiple hallmark capabilities by supplying these bioactive molecules to the tumour microenvironment:
[…]
Hallmark 10: Tumor-Promoting Inflammation
Tumour associated inflammatory response has the unanticipated, paradoxical effect of enhancing tumourigenesis and progression.
Inflammation (largely innate immune system) can contribute to multiple hallmark capabilities by supplying these bioactive molecules to the tumour microenvironment:
**- Growth factors
- Proangiogenic factors
- Extracellular matrix modifying enzymes
- ROS (mutagenic)
Hallmark 1: Growth signal autonomy (IMPT)
What are the 5 ways that cancer cells can acquire the capacity to short-circuit growth control pathways? Give examples of each.
- […]
- […]
- […]
- […]
- […]
Hallmark 1: Growth signal autonomy (IMPT)
What are the 5 ways that cancer cells can acquire the capacity to short-circuit growth control pathways? Give examples of each.
- **Increase production of Growth Factors
- Glioblastoma (brain tumours) overexpressing PDGF -
**Amplification/change in structure of Growth Factor Receptors
- More growth factor receptors, or
- Constitutively activated growth factor receptor (ligand independent activation)
- Mutated RTKs constitute one of the biggest classes of oncogenes.
- EGFR, HER2, EGFR, KIT, PDGFR, ALK -
change in structure of Signal Transduction Proteins
- Constitutively activated signal transduction proteins
- **RAS, BRAF, PI3K, AKT, mTOR
** - ***Activation of Transcription factors
- Activation of MYC (master transcription factor of cell growth)(Burkitt lymphoma, neuroblastoma)
* - Dysfunction of Cell Cycle Regulators
- Activating mutations of cyclins and cyclin-dependent kinases (CDKs) are common occurances in cancer
Hallmark 2: evasion of growth inhibitory signals
What are the physiological mechanisms of TSG in preventing uncontrolled growth?
- […]
- […]
- […]
- […]
Hallmark 2: evasion of growth inhibitory signals
What are the physiological mechanisms of TSG in preventing uncontrolled growth?
- inhibit cell division/cell cycle progression
- ensure genomic stability
- trigger apoptosis
- promote differentiation
Hallmark 3: Evasion of apoptotic cell death
Cancer cells evolve a variety of strategies to limit or circumvent apoptosis.
Apoptosis is a cascade of events leading to the activation of […] and ending with cell death.
- Pro-apoptotic genes: bax,bak
- Anti-apoptotic genes: […], bcl-xl
Loss of […] leads to reduced function of pro-apoptotic genes bax,bak
Hallmark 3: Evasion of apoptotic cell death
Cancer cells evolve a variety of strategies to limit or circumvent apoptosis.
Apoptosis is a cascade of events leading to the activation of caspases and ending with cell death.
- Pro-apoptotic genes: bax,bak
- Anti-apoptotic genes: bcl2, bcl-xl
Loss of p53 leads to reduced function of pro-apoptotic genes bax,bak
Hallmark 4: Unlimited replicative potential
Normal cells only have a finite number of cell doublings due to shortening of telomeres. Once cells reach the Hayflick’s limit, cells go into senescence.
Cancer cells maintain the length of their telomeres through reactivation of […], and therefore possess this property of replicative immortality.
Hallmark 4: Unlimited replicative potential
Normal cells only have a finite number of cell doublings due to shortening of telomeres. Once cells reach the Hayflick’s limit, cells go into senescence.
Cancer cells maintain the length of their telomeres through reactivation of telomerase, and therefore possess this property of replicative immortality.
Hallmark 5: Angiogenesis
Cancer cells induce angiogenesis needed for tumour survival, expansion and metastasis.
Example of a pro-angiogenic factors
[…]
Example of anti-angiogenic factor
[…]
Hallmark 5: Angiogenesis
Cancer cells induce angiogenesis needed for tumour survival, expansion and metastasis.
Example of a pro-angiogenic factors
Vascular endothelial growth factor (VEGF)
Example of anti-angiogenic factor
***p53 protein (from TP53 gene)
*
Hallmark 6 : Invasion and Metastasis
In order to spread, tumour cells must interact with the extracellular matrix (ECM) at several stages in the invasion metastasis cascade:
- tumor growth
- […]
- […]
- cancer cell traverse interstitial connective tissue
- cancer cell gain access to the circulation by penetrating the vascular basement membrane
- cancer cells circulate as tumor emboli or single cells
- cancer cells extravasate at distant site
- angiogenesis
- growth
Hallmark 6 : Invasion and Metastasis
In order to spread, tumour cells must interact with the extracellular matrix (ECM) at several stages in the invasion metastasis cascade:
- tumor growth
- loosening of tumor cells (by E-cadherin inactivation) and become mobile (by Epithelial-Mesenchymal Transition (EMT))
- cancer cells breach underlying basement membrane (by secretion of metalloproteinase)
- cancer cell traverse interstitial connective tissue
- cancer cell gain access to the circulation by penetrating the vascular basement membrane
- cancer cells circulate as tumor emboli or single cells
- cancer cells extravasate at distant site
- angiogenesis
- growth
Came out in 17/18 CA1 MEQ~
“E-cadherin is one of the most important molecules in cell-cell adhesion in epithelial tissues”
“The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types.”
Hallmark 7: Avoiding Immune Destruction (IMPT!!!)
Tumour antigens are presented on the cell surface by MHC class […] molecules and are recognized by CD[…] CTLs.
However, tumours may avoid the immune system by several mechanisms:
- Loss of […]
- Loss or reduced expression of […]
- Secretion of […] from the tumour
- Expression of inhibitory cell surface proteins eg […]
- Promote other cellular suppressors of immune responses, such as […]
Hallmark 7: Avoiding Immune Destruction** (IMPT!!!)**
Tumour antigens are presented on the cell surface by MHC class I molecules and are recognized by CD**8+ **CTLs.
However, tumours may avoid the immune system by several mechanisms:
- Loss of tumour specific antigens
- Loss or reduced expression of* MHC class I*
- Secretion of immunosuppressive factors (e.g. TGF β) from the tumour
- Expression of inhibitory cell surface proteins eg CTLA-4, PD-L1
- Promote other cellular suppressors of immune responses, such as regulatory T cells
Hallmark 8: Reprogamming Energy Metabolism
Unlike normal cells, cancer cells carry out glycolysis, even in the presence of oxygen (aerobic glycosis or […] effect)
Increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, enabling the synthesis of macromolecules and organelles that are needed for rapid cell growth
Hallmark 8: Reprogamming Energy Metabolism
Unlike normal cells, cancer cells carry out glycolysis, even in the presence of oxygen (aerobic glycosis or Warburg effect)
Increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, enabling the synthesis of macromolecules and organelles that are needed for **rapid cell growth
**
Hallmark 9: Genome Instability
Genomic instability in cancer cells can either be due to a break down of […] or breakdown of […]
Hallmark 9: Genome Instability
Genomic instability in cancer cells can either be due to a break down of **DNA repair mechanism (DNA MMR deficiency) **or breakdown of surveillance mechanism (p53 loss of function mutations)
Important DNA repair factors: […]
Important DNA repair factors: MSH2, MSH6 and MLH1, PMS2
In 85% of follicular B cell lymphomas, the anti apoptotic gene […] is activated by the t([…];[…]) translocation
In 85% of follicular B cell lymphomas, the anti apoptotic gene BCL2 is activated by the t(14;18) translocation
Invasive breast carcinoma (when tumor over-expresses HER2 receptor) treatment: […]
Colorectal carcinoma (when it over-expresses EGFR) (NOT when there is KRAS or BRAF mutation) treatment: […]
Invasive breast carcinoma (when tumor over-expresses HER2 receptor) treatment: Monoclonal antibody: Herceptin
Colorectal carcinoma (when it over-expresses EGFR) (NOT when there is KRAS or BRAF mutation) treatment: Monoclonal antibody: Erbitux (cetuximab)/Vectibix (panitumumab)
Li Fraumeni syndrome is characterized by germline mutation of […] gene. Patients have 25-fold increase risk of developing cancer before 50 years old.
[…] gene function mainly to […]
Li Fraumeni syndrome is characterized by germline mutation of TP53 gene. Patients have 25-fold increase risk of developing cancer before 50 years old.
TP53 gene function mainly to sense DNA damage and respond by triggering DNA repair/apoptosis
Mismatch repair (MMR) is an essential process for maintaining […] and is executed by MMR proteins (MSH2,MSH6,MLH1,PMS2) which work together.
The loss of MMR proteins (MMR deficiency) can occur through
- […]
- […]
The genomes of patients with MMR deficiency show […], characterized by changes in […] of short tandem repeating sequences throughout the genome.
Mismatch repair (MMR) is an essential process for maintaining genomic stability and is executed by MMR proteins (MSH2,MSH6,MLH1,PMS2) which work together.
The loss of MMR proteins (MMR deficiency) can occur through
- Loss of function mutations (usually in heritable condition such as HNPCC)
- **Epigenetic mechanisms such as DNA methylation (15% of sporadic colorectal carcinoma) **
The genomes of patients with MMR deficiency show microsatellite instability (MSI), characterized by changes in length of short tandem repeating sequences throughout the genome.
MSI-H (microsatellite instability high) phenotype, other than being observed in HNPCC, can also be observed sporadically in many cancer types, including 15% of colorectal carcinoma.
Usually caused by […] of MLH1 (one of the MMR genes) gene expression, thus leading also to MMR deficiency.
There is usually […] gene mutation for this case.
MSI-H (microsatellite instability high) phenotype, other than being observed in HNPCC, can also be observed sporadically in many cancer types, including 15% of colorectal carcinoma.
Usually caused by epigenetic inactivation (by hypermethylation) of MLH1 (one of the MMR genes) gene expression, thus leading also to MMR deficiency.
There is usually NO gene mutation for this case.
Name the 10 hallmarks of cancer! (vvvv IMPT)
Six established hallmarks
1. […]
2. […]
3. […]
4. […]
5. […]
6. […]
Two emerging hallmarks
7. […]
8. […]
Two enabling characteristics
9. […]
10. […]
Name the 10 hallmarks of cancer! (vvvv IMPT)
Six established hallmarks
1. growth signal autonomy
2. evasion of growth inhibitory signals
3. evasion of apoptotic cell death
4. unlimited replicative potential
5. angiogenesis
6. invasion and metastasis
Two emerging hallmarks
7. avoiding immune destruction
8. reprogamming energy metabolism
Two enabling characteristics
9. genome instability
10. tumor-promoting inflammation
Oncogenes are activated by […] abberation
Tumor Suppresor genes are inactivated by […] abberations (Knudson’s 2-hit hypothesis)
Oncogenes are activated by single “gain of function” abberation
Tumor Suppresor genes are inactivated by two “loss of function” (thus they behave recessively) abberations (Knudson’s 2-hit hypothesis)
p53 is kept at low level by regulatory protein […].
when there is
1. […]
2. […]
OR
3. […],
they are sensed by […] which phosphorylates p53/[…] proteins, disrupting the binding. This allows p53 to accumulate.
accumulation of p53 causes:
1. […] (cell cycle arrest) (pausing for repair)
2. […]
3. […]
4. […]
5. […]
p53 is kept at low level by regulatory protein MDM2 (a ubiquitin ligase).
when there is
1. DNA damage
2. hypoxia
OR
3. inappropriate oncogene signalling,
they are sensed by **ATM/ATR **which phosphorylates p53/MDM2 proteins, disrupting the binding. This allows p53 to accumulate.
accumulation of p53 causes:
1. activates genes p21 (CDK inhibitor) (cell cycle arrest) (pausing for repair)
2.* activates GADD45 (DNA repair)*
3. activates pro-apoptosis gene BAX (if repair fails)
4. senescence (if repair fails)
5.* inhibition of angiogenesis*
pathogenesis of HPV causing cervical cancer:
- […]
- […]
- […]
- […]
- […]
pathogenesis of HPV causing cervical cancer:
- **Infects epithelial cells; viral genome transported into nucleus **
- **Sophisticated transcriptional cascade occurs as host keratinocyte begins to divide and become increasignly differentiated in higher layers **
- Viral genome integration into host genome increases expression of E6 and E7 proteins in the viral DNA (note: this is NOT insertional mutagenesis)
- E6 protein inactivates p53; E7 protein inactivates pRB, which are important tumour suppressor genes within the cell
- **Loss of regulation of the cell cycle at checkpoints: damaged DNA is allowed to be replicated and over time, mutations in other genes accumulate to cause the cells to become cancerous **
proteins that regulate normal growth such as
- growth factors
- growth receptors
- cell signalling molecules
- transcription factors
- cell cycle components
are encoded by […].
A gain of function/activating mutations turns these proto-oncogenes into […], which produces […] that stimulate cell division or proliferation even in the […] of proper growth signals
proteins that regulate normal growth such as
- growth factors
- growth receptors
- cell signalling molecules
- transcription factors
- cell cycle components
are encoded by proto-oncogenes.
A gain of function/activating mutations turns these proto-oncogenes into oncogenes, which produces **abberrant protein (oncoproteins) **that stimulate cell division or proliferation even in the absence of proper growth signals
Proto-oncogenes are normal cellular genes whose products […] normal cellular growth
Tumour suppressor genes (TSG) are normal cellular genes whose products […] normal cellular growth
Oncogenes are typically mutated version of proto-oncogenes that produce an aberrant protein (oncoprotein) that stimulates cell division or proliferation, even in the […] of proper growth signal
Proto-oncogenes are normal cellular genes whose products promote normal cellular growth
Tumour suppressor genes (TSG) are normal cellular genes whose products suppress normal cellular growth
Oncogenes are typically mutated version of proto-oncogenes that produce an aberrant protein (oncoprotein) that stimulates cell division or proliferation, even in the absence of proper growth signal
PTEN gene is a […] which inhibits […] signalling
It works by dephosphorylating PIP3 to […].
PTEN gene is a TSG which inhibits PI3K/AKT signalling
It works by dephosphorylating PIP3 to PIP2.
Retinoblastoma (RB) regulates […] checkpoint by binding to […] (a transcription factor for genes such as […]), needed for S phase, preventing transcription of genes that are needed for DNA replication. so cells are arrested at G1.
In resting or quiescent cell, RB is […]
In this state, RB is able to bind to […] and prevent its activation
phosphorylation of Retinoblastoma is inhibited by […]
Retinoblastoma (RB) regulates G1/S **checkpoint by binding to *E2F (a transcription factor for genes such as *cyclins and cyclin dependent kinases), needed for S phase, preventing transcription of genes that are needed for DNA replication. so cells are arrested at G1.
In resting or quiescent cell, RB is hypophosphorylated
In this state, RB is able to bind to E2F and prevent its activation
phosphorylation of Retinoblastoma is inhibited by cyclin-dependent kinase inhibitors (eg. p16 and p21)
The most important growth factor receptor is probably the […].
It recruits (by phosphorylation) other signalling molecules like PI3K and Ras
The most important growth factor receptor is probably the receptor tyrosine kinase (RTK).
It recruits (by phosphorylation) other signalling molecules like PI3K and Ras
tumors become more aggressive and malignant over time because […]
tumors become more aggressive and malignant over time because of accumulation of mutations that accelerate growth, invasiveness and ability to metastasize.
Impt to understand that the acquisition of malignant phenotype is a MULTISTEP process involving progressive accumulation of genetic mutations
What are the common defining features of cancers?
[…]
What are the common defining features of cancers?
- Unregulated cell growth
- Invasion
- Metastasis
What are the mechanisms by which retinoblastoma proteins loses its antiproliferative effect?
- […]
- […]
- […]
- […]
What are the mechanisms by which retinoblastoma proteins loses its antiproliferative effect?
1.* Loss of function mutations affecting RB genes*
2. Viral oncoproteins that bind and inhibit RB (E7 protein of HPV)
3. Gene amplifications of CDK4 and cyclin D genes
4. Loss of cyclin dependent kinase inhibitors (p16/INK4a)
What are the mechanisms of oncogenic alteration of receptor tyrosine kinases (RTKs)?
- […]
- […]
- […]
What are the mechanisms of oncogenic alteration of receptor tyrosine kinases (RTKs)?
- ***Amplification or over-expression of normal receptors (EGFR, HER2)
- point mutation/deletions in tyrosine kinase domain (EGFR, KIT, PDGFRA)
- Gene rearrangement/translocation (ALK,ROS1)*
